A chiron approach to (-)-tetrahydrolipstatin

Article abstract of DOI:10.1055/s-2006-950325

An efficient chiron approach to the total synthesis of (-)- tetrahydrolipstatin is described. The main features of the synthetic strategy, which starts from tri-O-acetyl-D-glucal, are copper-mediated C-C bond formation, Frater alkylation, and Barton-McCombie deoxygenation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950325

3888
PAPER
A Chiron Approach to (–)-Tetrahydrolipstatin
A
Chiron
.Approach to
S
(–)-Tetrahydr
.
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160387; E-mail: yadavpub@iict.res.in
Received 28 June 2006; revised 4 July 2006
developed by our group,3 to afford methyl acetal 3. The
methyl acetal 3 was subjected to methanolysis and subse-
quent selective protection of the 1,3-diol part to furnish 4
in 66% overall yield. Compound 4 was protected its ben-
zyl ether 5 and then subjected to benzylidene acetal cleav-
age with 4-toluenesulfonic acid in methanol to afford 1,3-
diol 6, which was selectively protected with a tert-bu-
tyldimethylsilyl group at the primary hydroxy group to
give 7 and the secondary hydroxy group was then protect-
ed as its xanthate ester to afford 8 in 40% yield over four
steps. Now the stage is set for Barton–McCombie deoxy-
genation. Accordingly, compound 8 was treated with
tributyltin hydride and a catalytic amount of 2,2¢-azo-
bis(isobutyronitrile) in dry toluene under reflux condi-
tions to afford the deoxygenated compound 9.4
Abstract: An efficient chiron approach to the total synthesis of (–)-
tetrahydrolipstatin is described. The main features of the synthetic
strategy, which starts from tri-O-acetyl-D-glucal, are copper-
mediated C–C bond formation, Frater alkylation, and Barton–
McCombie deoxygenation.
Key words: (–)-tetrahydrolipstatin, anti-obesity, tri-O-acetyl-D-
glucal, Frater alkylation
(–)-Tetrahydrolipstatin 1, a b-lactone, is a potent and irre-
versible inhibitor of pancreatic lipase; it is the saturated
analogue of lipstatin and was first isolated from Strepto-
myces toxytricini in 1987.1 Recently, it has been marketed
in several countries as an anti-obesity agent under the
name Xenical. The key to the biological activity of the lip-
statins is the b-lactone moiety, which features anti stereo-
chemistry about the ring. Due to its biological properties,
tetrahydrolipstatin has been the target of many synthetic
organic chemists since its isolation.2
The tert-butyldimethylsilyl group of compound 9 was
removed and the resulting alcohol 10 was treated with
4-toluenesulfonyl chloride and triethylamine in dichlo-
romethane to afford the corresponding tosylate 11, which
was treated with n-decylmagnesium bromide and catalyt-
ic copper(I) bromide to obtain the coupled product 12.5
Compound 12 could also be obtained from alcohol 10 via
conversion to the corresponding triflate and copper-medi-
ated Grignard displacement.6
Our retrosynthetic analysis is depicted in Scheme 1. Thus,
(–)-tetrahydrolipstatin (1) could be obtained in a three-
step sequence from b-hydroxy acid 17. It is envisaged that
the hydroxy acid 17 could be obtained from d-lactone 14.
The d-lactone 14 could be, in turn, obtained from tri-O-
acetyl-D-glucal, with methanol addition and Barton–
McCombie deoxygenation as the key transformations.
The methyl acetal of 12 was converted into lactol 13 by
treatment with 80% aqueous acetic acid, which in turn
was subjected to oxidation with Dess–Martin
periodinane7 to yield lactone 14. The b-lactone 14 was
opened in the presence of triethylamine in methanol to
The synthesis begins by C-glycosidation of tri-O-acetyl-
D-glucal (2) by addition of methanol and cerium(III) chlo-
ride heptahydrate/sodium iodide in acetonitrile, a method
NH-CHO
O
MOMO
OH
n-C11H23
O
O
O
CO2H
O
O
n-C11H23
n-C11H23
n-C6H13
n-C6H13
17
OBn
O
14
(–)-tetrahydrolipstatin 1
n-C11H23
O
OMe
O
OMe
AcO
OTBS
AcO
OBn
OBn
OAc
12
9
2
Scheme 1
SYNTHESIS 2006, No. 22, pp 3888–3894
x
x
.x
x
.
2
0
0
6
Advanced online publication: 20.10.2006
DOI: 10.1055/s-2006-950325; Art ID: Z13306SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
A Chiron Approach to (–)-Tetrahydrolipstatin
3889
O
O
OMe
O
OMe
AcO
AcO
AcO
AcO
i
ii, iii
O
v
Ph
O
OAc
OAc
OR
2
3
4
5
R = H
R = Bn
iv
TBSO
S
O
OMe
O
OMe
O
OMe
TBSO
viii
RO
vii
HO
MeS
O
OBn
OBn
OBn
9
8
6
7
R = H
vi
R = TBS
Scheme 2 Reagents and conditions: (i) CeCl3–NaI, MeCN, MeOH, reflux, 3 h, 87%; (ii) NaOMe, MeOH, r.t., 2 h; (iii) PhCH(OMe)2, PTSA
(cat.), toluene, reflux, 2 h, 66% for 2 steps; (iv) NaH, BnBr, TBAI (cat.), THF, reflux, 6 h, 78%; (v) PTSA (cat.), MeOH, overnight, 79%; (vi)
TBSCl, imidazole, CH2Cl2, 0 °C to r.t., 4 h, 83%; (vii) NaH, CS2, MeI, 0 °C to r.t., overnight, 78%; (viii) n-Bu3SnH, AIBN (cat.), toluene, reflux,
6 h, 79%.
yield the corresponding d-hydroxy ester, which without amide in tetrahydrofuran, followed by addition of n-hexyl
workup, on removal of methanol under reduced pressure iodide to the dianion to give 16 as the major diastereomer
was protected as its methoxymethyl ether 15 in the pres- in 75% yield after a flash column chromatography.8 The
ence of N,N-diisopropylethylamine and methoxymethyl crude product of the reaction revealed ~2% of the other
chloride in dichloromethane. Attempts made to isolate the diastereomer.
methanol addition product, the d-hydroxy ester, were un-
Hydroxy ester 16 was converted to b-lactone 18 by hy-
successful as it cyclized back to lactone 14. The methyl
drolysis of ester group with lithium hydroxide followed
ester 15 was hydrogenated with palladium(II) hydroxide
by exposure of acid 17 to benzenesulfonyl chloride in py-
Pd(OH)2 in ethyl acetate to afford a b-hydroxy ester. The
ridine. Deprotection of the methoxymethyl ether of b-lac-
key step, stereocontrolled alkylation, was effected by
tone 18 with boron trifluoride–diethyl ether complex and
treating the b-hydroxy ester with lithium diisopropyl-
n-C11H23
O
OMe
OR
O
OMe
O
RO
iv
TsO
ii a
ii b
OBn
OBn
OBn
R = OMe
R = H
11
12
13
9
R = TBS
iii
i
10 R = H
MOMO
n-C11H23
OH
O
O
v
MOMO
n-C11H23
OBn
COOR
vii
vi,
n-C11H23
CO2Me
n-C6H13
OBn
14
15
R = Me
R = H
16
17
viii
O
OR
O
ix
xi
(–)-tetrahydrolipstatin 1
n-C11H23
n-C6H13
R=MOM
R=H
18
19
x
Scheme 3 Reagents and conditions: (i) TBAF, THF, 0 °C to r.t., 2 h, 98%; (ii) (a) TsCl, Et3N, DMAP (cat.), CH2Cl2, 0 °C to r.t., 2 h, 92%;
(ii) (b) n-C10H21MgBr, CuBr (cat.), THF, 0 °C to r.t., 5 h, 76%; (iii) 80% aq AcOH, reflux, 6 h, 72%; (iv) Dess–Martin periodinane, CH2Cl2,
0 °C to r.t., 2 h, 84% (v) Et3N, MeOH, 0 °C to r.t., 12 h, then MOMCl, DIPEA, CH2Cl2, 0 °C to r.t., 12 h, 71%; (vi) Pd(OH)2/C, EtOAc, 12 h,
94%; (vii) LDA, n-C6H13I, HMPA, THF, –78 °C, 3 h, 75%; (viii) LiOH, THF–H2O, (4:1), 0 °C to r.t., 12 h, 88%; (ix) PhSO2Cl, pyridine, 12 h,
0 °C, 76%; (x) BF3·OEt2, (CH2SH)2, 0 °C to r.t., 1 h, 88%; (xi) DIAD, TPP, N-formyl-L-leucine, 0 °C to r.t., 2 h, 90%.
Synthesis 2006, No. 22, 3888–3894 © Thieme Stuttgart · New York

3890
J. S. Yadav et al.
PAPER
ethane-1,2-dithiol9 in dichloromethane produced alcohol
19 which on esterification with (S)-N-formyl-L-leucine
under Mitsunobu conditions10 furnished (–)-tetrahydro-
lipstatin (1). The spectroscopic and physical data of 1
were in good agreement with those in literature.
filtered off, and the soln was diluted with CH2Cl2 and H2O. The
phases were separated and the aqueous phase was extracted with
CH2Cl2. The combined organic extracts were washed with H2O,
dried (MgSO4) and filtered and the solvents were evaporated to give
crude acetal. Column chromatography afforded the pure acetal 4 as
colorless needles; yield: 7.4 g (66%); mp 153–154 °C.
[a]D20 +93.74 (c 7.0, CHCl3).
In conclusion, an efficient total synthesis of (–)-tetrahy-
drolipstatin using the chiron approach has been achieved.
Simple manipulations of commercially available, inex-
pensive tri-O-acetyl-D-glucal led to the complex and de-
manding anti-obesity drug (–)-tetrahydrolipstatin (1).
Rf = 0.4 (silica gel, 40% EtOAc–hexane).
IR (KBr): 3358 (OH), 2930, 1457, 1380, 1114, 1022 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.32 (m, 5 H), 5.50 (s, 1 H),
4.74 (d, J = 3.7 Hz, 1 H), 4.20 (m, 1 H), 4.08 (m, 1 H), 3.70 (m, 2
H), 3.38 (m, 1 H), 3.32 (s, 3 H), 2.47 (d, 1 H, OH), 2.16 (dd,
J = 12.8, 5.3 Hz, 1 H), 1.71 (ddd, J = 13.6, 11.3, 3.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 137.40, 129.17, 128.30, 126.35,
102.00, 99.03, 83.87, 68.98, 65.63, 62.55, 54.75, 37.33.
MS (ESI): m/z = 267 [M+ + H].
Melting points were recorded on a Fisher John melting point appa-
ratus. IR spectra were recorded on a Perkin Elmer Infrared-683
spectrophotometer with NaCl optics. 1H NMR and 13C NMR spec-
tra were recorded in CDCl3 on Varian Gemini 200 and AV-300
spectrometers. Optical rotations were measured on JASCO DIP-
360 digital polarimeter. Analytical TLC was performed on precoat-
ed silica gel-60 F254 (0.5 mm) glass plates. Column chromatography
was performed using silica gel (60–120 mesh) and the column was
generally eluted with EtOAc–petroleum ether.
(4aR,6S,8R,8aS)-8-(Benzyloxy)-6-methoxy-2-phenylhexa-
hydropyrano[3,2-d][1,3]dioxin (5)
A magnetically stirred suspension of dry, oil-free NaH (1.24 g, 51.8
mmol) in anhyd THF (5 mL) at 0 °C was treated with the alcohol 4
(6.9 g, 25.9 mmol) in THF (25 mL). After 15 min, BnBr (3.38 mL,
28.5 mmol) was added followed by catalytic TBAI (479 mg). The
mixture was brought to r.t. and stirred at reflux for 4 h, cooled to
0 °C, and treated slowly with sat. aq NH4Cl (20 mL). The product
was extracted into EtOAc (2 × 100 mL); the combined extracts
were dried (Na2SO4) and concentrated and the residual oil was pu-
rified by chromatography (silica gel) to afford 5 as white solid;
yield: 6.64 g (78%); mp 95–96 °C.
(2R,3R,4R,6S)-3,4-Diacetoxy-2-(acetoxymethyl)-6-methoxy-
tetrahydro-2H-pyran (3)
A mixture of 3,4,6-tri-O-acetyl-D-glucal (2; 20.6 g, 75.6 mmol),
MeOH (6.13 mL, 151.2 mmol), CeCl3·7 H2O (42.32g, 113.6 mmol),
and NaI (17.02 g, 113.6 mmol) in MeCN (150 mL) was stirred at
reflux temperature for 6 h. The mixture was diluted with H2O (150
mL) and extracted with EtOAc (3 × 100 mL). The combined organ-
ic layers were dried (anhyd Na2SO4), concentrated in vacuo, and pu-
rified by column chromatography to give methyl glucoside 3 as a
colorless oil; yield: 20.0 g (87%); 10:1 mixture of anomers.
[a]D25 +71.35 (c 1.5, CHCl3).
Rf = 0.6 (silica gel, 30% EtOAc–hexane).
IR (neat): 2973, 1219, 1054, 1013, 772 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.45–7.28 (m, 10 H), 5.56 (s, 1 H),
4.81–4.61 (m, 3 H), 4.20 (q, J = 8.3, 3.0 Hz, 1 H), 3.97–3.89 (m, 1
H), 3.74–3.70 (m, 2 H), 3.67–3.57 (m, 1 H), 3.30 (s, 3 H), 2.20 (dd,
J = 12.9, 4.53 Hz, 1 H), 1.73 (ddd, J = 12.8, 10.5, 3.7 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 128.0, 127.6, 127.4, 126.9, 126.7,
125.4, 100.6, 98.3, 83.2, 72.1, 68.4, 62.2, 53.9, 35.8.
MS (ESI): m/z = 357 [M+ + H].
HRMS (ESI): m/z [M+ + H] calcd for C21H25O5: 357.1701; found:
Data for the major anomer:
[a]D20 +130.76 (c 1.5, CHCl3).
Rf = 0.4 (silica gel, 30% EtOAc–hexane).
IR (neat): 2947, 2838, 1745 (C=O), 1231, 1049 cm–1.
1H NMR (300 MHz, CDCl3): d = 5.25 (ddd, J = 11.7, 9.4, 5.3 Hz, 1
H), 4.93 (t, J = 9.8 Hz, 1 H), 4.81 (d, J = 3.4 Hz, 1 H), 4.28 (dd,
J = 12.0, 4.53 Hz, 1 H), 4.01 (dd, J = 12.0, 2.2 Hz, 1 H), 3.88 (ddd,
J = 10.2, 4.5, 2.2 Hz, 1 H), 3.35 (s, 3 H), 2.22 (ddd, J = 12.8, 5.7,
1.1 Hz, 1 H), 2.08 (s, 3 H), 2.02 (s, 3 H), 2.00 (s, 3 H), 1.78 (ddd,
J = 12.8, 11.7, 3.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 170.01, 169.46, 169.22, 97.43,
68.83, 68.48, 67.17, 61.88, 54.22, 34.33, 20.24, 20.04.
MS (ESI): m/z = 327 (M+ + Na).
357.1700.
(2R,3S,4R,6S)-4-(Benzyloxy)-2-(hydroxymethyl)-6-methoxy-
tetrahydro-2H-pyran-3-ol (6)
To 5 (6.7 g, 18.8 mmol) in MeOH (15 mL) was added catalytic
PTSA (178 mg) and the mixture was stirred for 12 h. It was
quenched by addition of sat. aq NaHCO3 (5 mL), MeOH was evap-
orated under reduced pressure, and the aqueous phase was extracted
with EtOAc (2 × 75 mL). The organic extracts were washed with
brine (20 mL) and dried (anhyd Na2SO4). The solvent was evapo-
rated and the residue was purified by column chromatography to af-
ford pure diol 6 as a greasy solid; yield: 3.98 g (79%); mp 38–40 °C.
HRMS: m/z [M+ + Na] calcd for C13H20NaO8: 327.1055; found:
327.1058.
(4aR,6S,8R,8aS)-6-Methoxy-2-phenylhexahydropyrano[3,2-
d][1,3]dioxin-8-ol (4)
To a soln of methyl glucoside 3 (12.8 g, 42.1 mmol) in MeOH (100
mL) was added 1 M NaOMe in MeOH (6.6 mL, 0.660 mmol). The
mixture was stirred at r.t. for 1 h and the reaction was quenched by
addition of Amberlyst. The mixture was filtered and concentrated
under reduced pressure to give the crude triol, which was used in the
next step without further purification.
[a]D25 +62.77 (c 5.0, CHCl3).
Rf = 0.2 (silica gel, 60% EtOAc–hexane).
IR (neat): 3417 (OH), 1618, 1352, 1063, 772 cm–1.
A mixture of the crude triol, toluene (50 mL), benzaldehyde di-
methyl acetal (6.1 mL, 41.1 mmol), and PTSA (325 mg, 1.7 mmol)
was heated at reflux in a Soxhlet containing freshly activated pow-
dered 4 Å molecular sieves (10 g) under an N2 flow for 5 h. After 5
h, another batch of 4 Å molecular sieves (10 g) was placed in the
Soxhlet extractor and reflux was continued for 1 h. The solid was
1H NMR (200 MHz, CDCl3): d = 7.31–7.26 (m, 5 H), 4.77 (d,
J = 3.1 Hz, 1 H), 4.58 (q, J = 28.1, 11.7 Hz, 2 H), 3.78–3.69 (m, 3
H), 3.55–3.52 (m, 2 H), 3.31 (s, 3 H), 3.0 (br s, 1 H, OH), 2.37 (br
s, 1 H, OH), 2.22 (dd, J = 12.5, 4.6 Hz, 1 H), 1.57 (ddd, J = 14.8,
11.7, 3.1 Hz, 1 H).
Synthesis 2006, No. 22, 3888–3894 © Thieme Stuttgart · New York

PAPER
A Chiron Approach to (–)-Tetrahydrolipstatin
3891
13C NMR (75 MHz, CDCl3): d = 127.8, 127.0, 97.9, 76.3, 70.7, 70.6,
[a]D25 +71.68 (c 2.0, CHCl3).
70.4, 61.8, 54.0, 34.0.
Rf = 0.45 (silica gel, 10% EtOAc–hexane).
IR (neat): 2932, 2895, 1460, 1055, 831, 772 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28 (m, 5 H), 4.81 (d, J = 3.00
Hz, 1 H), 4.52 (m, 2 H), 3.82 (m, 1 H), 3.65 (m, 2 H), 3.53 (m, 2 H),
3.27 (s, 3 H), 2.08 (ddd, J = 16.6, 12.0, 4.53 Hz, 2 H), 1.50 (ddd,
J = 15.1, 11.3, 3.7 Hz, 1 H), 1.23 (q, J = 11.3 Hz, 1 H), 0.89 (s, 9 H),
0.05 (s, 6 H).
MS (ESI): m/z = 291 [M+ + Na].
HRMS (ESI): m/z [M+ + Na] calcd for C14H20NaO5: 291.1208;
found: 291.1206.
(2R,3S,4R,6S)-4-(Benzyloxy)-2-[(tert-butyldimethylsiloxy)meth-
yl]-6-methoxytetrahydro-2H-pyran-3-ol (7)
To a magnetically stirred soln of diol 6 (3.5 g, 13.0 mmol) in anhyd
CH2Cl2 (5 mL) and imidazole (1.77 g, 26.0 mmol) at 0 °C under an
N2 atmosphere was added TBSCl (1.96 g, 13.0 mmol); the mixture
was allowed to warm up to r.t. and it was stirred for 4 h. The mixture
was diluted with H2O (20 mL) and extracted with CH2Cl2 (2 × 20
mL). The combined organic layers were washed with brine (20
mL), dried (anhyd Na2SO4), and concentrated in vacuo to afford the
crude product. Column chromatography of the crude product af-
forded 7 as a colorless liquid; yield: 4.14 g (83%).
13C NMR (75 MHz, CDCl3): d = 128.24, 127.42, 99.02, 96.11,
70.83, 69.80, 68.62, 66.31, 54.30, 36.55, 34.42, 25.93, –5.29.
MS (ESI): m/z = 389 [M+ + Na].
HRMS: m/z [M+ + Na] calcd for C20H34NaO4Si: 389.2124; found:
389.2134.
(2S,4S,6S)-4-(Benzyloxy)-6-methoxytetrahydro-2H-pyran-2-
methanol (10)
[a]D25 +45.38 (c 3.75, CHCl3).
To a cold (0 °C), magnetically stirred soln of 9 (3.5 g, 9.56 mmol)
in anhyd THF (10 mL) was added 1.0 M TBAF in THF (19 mL,
19.1 mmol). The mixture was warmed to 25 °C, stirred for 2 h, treat-
ed with aq NH4Cl soln (30 mL), and extracted with EtOAc. The
combined organic layers were dried (Na2SO4) and concentrated.
The crude product was purified by chromatography (silica gel) to
give 10 as a clear, colorless oil; yield: 2.36 g (98%).
Rf = 0.5 (silica gel, 20% EtOAc–hexane).
IR (neat): 3478 (OH), 2931, 2896, 2857, 1464, 1053, 836, 777 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.31 (m, 5 H), 4.74 (d, J = 3.1 Hz,
1 H), 5.59 (q, J = 18.7, 11.7 Hz, 2 H), 3.80 (m, 3 H), 3.56 (m, 2 H),
3.29 (s, 3 H), 2.65 (br s, 1 H, OH), 2.17 (dd, J = 14.0, 4.6 Hz, 1 H),
1.55 (ddd, J = 13.2, 11.7, 3.9 Hz, 1 H), 0.89 (s, 9 H), 0.07 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 138.6, 128.4, 127.7, 98.4, 76.9,
72.5, 71.5, 71.2, 64.1, 54.5, 34.6, 25.9, –5.3.
MS (ESI): m/z = 383 [M+ + H].
HRMS (ESI): m/z [M+ + H] calcd for C20H35O5Si: 383.2253; found:
[a]D25 +110.6 (c 4.5, CHCl3).
Rf = 0.4 (silica gel, 50% EtOAc–hexane).
IR (neat): 3447, 2930, 1363, 1119, 1048, 737 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.31–7.27 (m, 5 H), 4.86 (d,
J = 2.5 Hz, 1 H), 4.52 (s, 2 H), 3.95–3.71 (m, 2 H), 3.58–3.53 (m, 2
H), 3.30 (s, 3 H), 2.32 (br s 1 H, OH), 2.17 (dd, J = 12.7, 4.2 Hz, 1
H), 1.99–1.91 (m, 1 H), 1.53 (dt, J = 12.7, 3.4 Hz, 1 H), 1.36 (q,
J = 11.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 138.4, 128.2, 127.3, 99.0, 70.4,
69.7, 68.4, 65.5, 54.4, 36.4, 33.5.
MS (ESI): m/z = 275 [M+ + Na].
HRMS (ESI): m/z [M+ + Na] calcd for C14H20NaO4: 275.1259;
383.2260.
(2R,3S,4R,6S)-4-(Benzyloxy)-2-[(tert-butyldimethylsiloxy)meth-
yl]-6-methoxy-3-{[(methylsulfanyl)carbothioyl]oxy}tetrahydro-
2H-pyran (8)
To a magnetically stirred suspension of NaH (460 mg, 19.2 mmol)
in CS2 (150 mL) was added a soln of 7 (3.7 g, 9.6 mmol) in CS2 (12
mL). After 4 h, neat MeI (3.02 mL, 48.4 mmol) was introduced via
syringe. The mixture was stirred for 12 h and then diluted with Et2O
(200 mL) and washed with H2O (100 mL) and aq NH4Cl soln (30
mL), dried (Na2SO4), and the solvent evaporated. The residue was
purified by chromatography to give xanthate 8 as a viscous yellow
liquid; yield: 3.56 g (78%).
found: 275.1252.
(2S,4S,6S)-4-(Benzyloxy)-2-methoxy-6-(tosyloxymethyl)tetra-
hydro-2H-pyran (11)
To soln of 10 (1.96 g, 7.77 mmol) in anhyd CH2Cl2 (15 mL) was
added Et3N (2.16 mL, 15.5 mmol) at 0 °C and this was followed by
addition of TsCl (1.63 g, 8.55 mmol). The mixture was allowed to
warm to r.t. and stirred for 3 h. The reaction was treated with aq 1
M HCl (12 mL) and extracted with CH2Cl2 (3 × 25 mL). The organ-
ic layer was washed with sat. aq NaHCO3 (20 mL) and H2O. The
combined organic phases were dried (Na2SO4) and concentrated un-
der reduced pressure. Flash chromatography of the crude product
afforded tosylate 11 as a colorless viscous liquid; yield: 2.9 g (92%).
[a]D25 +28.25 (c 5.0, CHCl3).
Rf = 0.5 (silica gel, 10% EtOAc–hexane).
IR (neat): 2929, 2856, 1463, 1363, 1217, 1057, 837, 777 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.28–7.24 (m, 5 H), 5.85 (t, J = 9.5
Hz, 1 H), 4.83 (d, J = 3.47 Hz, 1 H), 4.55 (q, J = 12.1 Hz, 2 H),
4.10–3.98 (m, 1 H), 3.87–3.75 (m, 1 H), 3.69–3.61 (m, 2 H), 3.34
(s, 3 H), 2.56 (s, 3 H), 2.27 (dd, J = 13.0, 5.2, 1 H), 1.78 (dt,
J = 11.2, 3.4 Hz, 1 H), 0.88 (s, 9 H), 0.05 (s, 6 H).
13C NMR (75 MHz, CDCl3): d = 215.4, 138.2, 128.2, 127.5, 97.9,
80.3, 74.4, 71.7, 71.1, 62.8, 54.5, 35.5, 25.9, 19.2, 18.3, –5.27, –
5.36.
[a]D25 +77.04 (c 4.1, CHCl3).
Rf = 0.4 (silica gel, 30% EtOAc–hexane).
IR (neat): 2933, 1362, 1177, 772 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.79 (d, J = 8.4 Hz, 2 H), 7.34–
7.27 (m, 7 H), 4.77 (d, J = 2.5 Hz, 1 H), 4.49 (s, 2 H), 4.00–3.91 (m,
2 H), 3.88–3.72 (m, 2 H), 3.23 (s, 3 H), 2.46 (s, 3 H), 2.15–1.94 (m,
2 H), 1.47 (ddd, J = 1.52, 12.7, 3.4 Hz, 1 H), 1.23 (q, J = 11.8 Hz, 1
H).
13C NMR (75 MHz, CDCl3): d = 129.6, 128.2, 127.8, 127.3, 99.0,
71.9, 70.1, 69.7, 65.6, 54.5, 36.1, 33.5, 21.4.
MS (ESI): m/z = 495 [M+ + Na].
[(2S,4S,6S)-4-(Benzyloxy)-2-[(tert-butyldimethylsiloxy)meth-
yl]-6-methoxytetrahydro-2H-pyran (9)
To a magnetically stirred soln of xanthate 8 (3.1 g, 6.56 mmol) and
AIBN (ca. 30 mg) in anhyd toluene (20 mL) was added Bu3SnH (8.7
mL, 32.8 mmol). The resulting soln was stirred at reflux tempera-
ture for 1.5 h. The reaction contents were cooled, concentrated in
vacuo, and flushed rapidly through a short column of silica gel to af-
ford 9 as a clear, colorless oil; yield: 1.89 g (79%).
MS (ESI): m/z = 429 [M+ + Na].
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J. S. Yadav et al.
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HRMS (ESI): m/z [M+ + Na] calcd for C21H26NaO6S: 429.1347;
1 H), 1.61–1.55 (m, 2 H), 1.34– 1.18 (m, 18 H), 0.88 (t, J = 6.8 Hz,
found: 429.1344.
3 H).
13C NMR (75 MHz, CDCl3): d = 170.3, 137.6, 128.5, 127.8, 127.5,
(2S,4S,6R)-4-(Benzyloxy)-2-methoxy-6-undecyltetrahydro-2H-
pyran (12)
77.0, 70.3, 36.7, 35.5, 31.8, 29.5, 29.3, 24.8, 22.6, 14.0.
MS (ESI): m/z = 361 (M+ + H).
HRMS (ESI): m/z [M+ + H] calcd for C23H37O3: 361.2742; found:
To a suspension of CuBr (170 mg, 1.2 mmol) in THF (10 mL) at
0 °C was added 0.67 M n-C10H21MgBr in Et2O (13 mL, 8.71 mmol),
followed by monotosylate 11 (2.5 g, 6.15 mmol) in THF (25 mL);
the mixture was stirred at r.t. for 5 h. The reaction was quenched
with sat. aq NH4Cl soln and the insoluble residue was removed by
filtration through Celite. The filtrate was concentrated and the resi-
due was poured into Et2O. The organic layer was rinsed with H2O
and sat. brine (20 mL). Following solvent removal, the crude prod-
uct was purified by column chromatography to give 12 as a color-
less oil; yield: 1.76 g (76%).
361.2747.
Methyl (3S,5R)-3-(Benzyloxy)-5-(methoxymethoxy)hexa-
decanoate (15)
To the lactone 14 (1.2 g, 3.33 mmol) in anhyd MeOH (8 mL) was
added Et3N (2.32 mL, 16.6 mmol) at r.t. and the mixture was stirred
at this temperature for 10 h. The MeOH was removed under reduced
pressure, anhyd CH2Cl2 was added, and the soln cooled to 0 °C. The
DIPEA (1.73 mL, 10.0 mmol), DMAP (7 mg), and MOMCl (536
mg, 6.6 mmol) were added sequentially at 0 °C and the mixture was
stirred at r.t. for 6 h. It was then diluted with H2O (15 mL) and ex-
tracted with CH2Cl2 (2 × 15 mL) and the combined extracts were
washed with H2O (10 mL) and brine (10 mL). The solvent was
evaporated in vacuo and the crude product was subjected to column
chromatography to afford 15 as colorless oil; yield: 1.03 g (71%).
[a]D25 +54.26 (c 2.2, CHCl3).
Rf = 0.7 (silica gel, 30% EtOAc–hexane).
IR (neat): 2933, 1659, 1391, 770 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.34–7.23 (m, 5 H), 4.82 (d,
J = 3.0 Hz, 1 H), 4.55–4.54 (m, 2 H), 3.87–3.76 (m, 1 H), 3.63 (t,
J = 9.8 Hz, 1 H), 3.30 (s, 3 H), 2.16 (dd, J = 12.0, 3.7 Hz, 1 H),
2.03–1.99 (m, 1 H), 1.56–1.24 (m, 22 H), 0.91 (t, J = 6.0 Hz, 3 H).
[a]D25 –24.46 (c 3.3, CHCl3).
13C NMR (75 MHz, CDCl3): d = 128.3, 127.5, 99.1, 77.1, 69.8, 67.6,
Rf = 0.9 (silica gel, 20% EtOAc–hexane).
IR (neat): 2926, 2854, 1740 (C=O), 1459, 1038, 740 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.31–7.28 (m, 5 H), 4.59–4.46 (m,
4 H), 4.05–3.97 (m, 1 H), 3.72–3.64 (m, 4 H), 3.34 (s, 3 H), 2.55 (m,
2 H), 1.75–1.43 (m, 2 H), 1.34–1.25 (m, 20 H), 0.88 (t, J = 6.0 Hz,
3 H).
54.4, 38.1, 36.5, 35.9, 31.9, 29.6, 29.3, 25.6, 22.6, 14.0.
MS (ESI): m/z = 399 (M+ + Na).
HRMS: m/z [M+ + Na] calcd for C24H40NaO3: 399.2875; found:
399.2865.
(2S,4S,6R)-4-(Benzyloxy)-6-undecyltetrahydro-2H-pyran-2-ol
(13)
13C NMR (75 MHz, CDCl3): d = 171.8, 128.3, 127.8, 127.6, 97.9,
75.2, 73.4, 71.6, 55.6, 51.6, 40.7, 40.1, 35.2, 31.9, 29.8, 29.6, 29.3,
24.9, 22.6, 14.1.
MS (ESI): m/z = 459 (M+ + Na).
HRMS: m/z [M+ + Na] calcd for C26H44NaO5: 459.3086; found:
A soln of methyl acetal 12 (1.39 g, 3.69 mmol) in 80% aq AcOH (25
mL) was refluxed for 4 h. The mixture was cooled to 0 °C, neutral-
ized by addition of solid NaHCO3, and extracted with CH2Cl2
(2 × 20 mL). The organic extracts were washed with H2O (2 × 10
mL), brine (10 mL), and dried (anhyd Na2SO4). Filtration and evap-
oration of the solvent followed by purification (column chromatog-
raphy) afforded pure lactol 13 as a syrupy liquid; yield: 0.96 g
(72%).
459.3107.
Methyl (3S,5R)-3-Hydroxy-5-(methoxymethoxy)hexadecanoate
Compound 15 (0.9 g, 2.06 mmol) in EtOAc (40 mL) was added
Pd(OH)2/C (250 mg) and the suspension was hydrogenated for 12
h. Removal of the catalyst by filtration and flash chromatography
gave alcohol as a colorless liquid; yield: 0.67 g (94%).
[a]D25 +6.24 (c 2.25, CHCl3).
Rf = 0.4 (silica gel, 30% EtOAc–hexane).
IR (neat): 3367, 2921, 2850, 1092, 741 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.30–7.27 (m, 5 H), 5.39 (br s, 1
H), 4.54 (s, 2 H), 3.93–3.83 (m, 1 H), 3.57– 3.46 (m, 1 H), 3.32–3.24
(m, 1 H), 2.34–2.15 (m, 2 H), 2.06–1.91 (m, 1 H), 1.52–1.15 (m, 21
H), 0.89 (t, J = 6.7 Hz, 3 H).
[a]D25 –42.89 (c 2.85, CHCl3).
Rf = 0.6 (silica gel, 20% EtOAc–hexane).
IR (neat): 3471, 2925, 2854, 1738 (C=O), 1461, 1153, 1038 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.63 (q, J = 9.0, 2.2 Hz, 2 H), 4.21
(m, 1 H), 3.77 (m, 1 H), 3.69 (s, 3 H), 3.39 (s, 3 H), 3.29 (br s, 1 H,
OH), 2.42 (m, 2 H), 1.55 (m, 4 H), 1.25 (m, 18 H), 0.88 (t, J = 6.8
Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 172.6, 96.2, 75.5, 64.7, 55.7, 51.4,
41.7, 41.1, 34.9, 31.8, 29.5, 25.1, 22.5, 13.9.
MS (ESI): m/z = 347 (M+ + H).
HRMS (ESI): m/z [M+ + Na] calcd for C19H38NaO5: 369.2616;
MS (ESI): m/z = 385 (M+ + Na).
(4S,6R)-4-(Benzyloxy)-6-undecyltetrahydro-2H-pyran-2-one
(14)
To a soln of lactol 13 (1.8 g, 4.9 mmol) in CH2Cl2 (20 mL) was add-
ed Dess–Martin periodinane (3.16 g, 7.45 mmol) at 0 °C and the
mixture was stirred for 1 h under argon. The mixture was poured
into 10% Na2S2O3 soln and extracted with Et2O. The organic layer
was washed with sat. aq NaHCO3 and brine, dried (MgSO4) and
concentrated in vacuo. Column chromatography of the residue (sil-
ica gel) afforded lactone 14 as a waxy solid; yield: 1.50 g (84%); mp
31–33 °C.
found: 369.2610.
Methyl (2S,3S,5R)-2-Hexyl-3-hydroxy-5-(methoxymeth-
oxy)hexadecanoate (16)
To a stirred soln (–50 °C) of LDA (2.5 mmol) [generated from 1.6
M n-BuLi in THF (2.7 mL) and i-Pr2NH (0.61 mL)] in THF (3 mL)
was quickly added a soln of methyl (3S,5R)-3-hydroxy-5-(meth-
oxymethoxy)hexadecanoate (600 mg, 1.73 mmol) in THF (6 mL).
The mixture was stirred at –50 °C for 1 h and then hexyl iodide
(1.47 g, 6.9 mmol) in HMPA (0.8 mL) was then added dropwise.
[a]D25 +10.14 (c 3.0, CHCl3).
Rf = 0.45 (silica gel, 30% EtOAc–hexane).
1H NMR (300 MHz, CDCl3): d = 7.31–7.25 (m, 5 H), 4.53 (q,
J = 11.3 Hz, 2 H), 4.10 (m, 1 H), 2.82 (dd, J = 16.6, 10.5 Hz, 1 H),
2.51 (dd, J = 17.3, 9.8 Hz, 1 H), 2.23 (d, J = 16.6 Hz, 1 H), 1.71 (m,
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A Chiron Approach to (–)-Tetrahydrolipstatin
3893
The resulting mixture was stirred at this temperature for 1 h,
warmed to –20 °C, again stirred for 1 h, warmed to 0 °C and stirred
for 1 h. The yellow mixture was diluted with Et2O (80 mL) and
poured in to sat. aq NH4Cl (50 mL). The aqueous layer was extract-
ed with Et2O (3 × 50 mL), the combined organic layers were
washed with H2O (15 mL) and brine (20 mL) and dried (Na2SO4),
and the solvent was removed in vacuo. Flash chromatography af-
forded the 16 as the major diastereomer; yield: 559.2 mg (75%).
1H NMR (300 MHz, CDCl3): d = 4.46–4.40 (m, 1 H), 3.84–3.72 (m,
1 H), 3.24–3.17 (dt, J = 7.55, 3.8 Hz, 1 H), 1.93–1.67 (m, 4 H),
1.46–1.40 (m, 2 H), 1.26 (m, 26 H), 0.88 (t, J = 6.0 Hz, 6 H).
13C NMR (75 MHz, CDCl3): d = 171.3, 75.1, 68.4, 56.8, 41.5, 38.3,
31.4, 31.7, 29.3, 26.3, 25.8, 22.3, 13.9.
MS (ESI): m/z = 355 (M+ + H).
(1S)-1-{[(2S,3S)-3-Hexyl-4-oxooxetan-2-yl]methyl}dodecyl
(2S)-2-(Formylamino)-4-methylpentanoate (1)
[a]D25 –3.91 (c 0.6, CHCl3).
Rf = 0.3 (silica gel, 10% EtOAc–hexane).
IR (neat): 3449, 2924, 2854, 1735 (C=O), 1460, 1159, 1037 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.67 (d, J = 8.4, Hz, 2 H), 3.96 (m,
1 H), 3.80 (m, 1 H), 3.70 (s, 3 H), 3.39 (s, 3 H), 2.47–2.36 (m, 1 H),
1.71–1.4 (m, 6 H), 1.25 (m, 26 H), 0.89–0.84 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 175.6, 96.3, 76.9, 68.9, 51.9, 39.5,
34.9, 31.5, 29.6, 29.1, 27.3, 25.2, 22.4, 13.9.
MS (ESI): m/z = 431 (M+ + H).
To a stirred mixture of 19 (25 mg, 0.07 mmol), Ph3P (22.2 mg, 0.08
mmol) and (S)-N-formyl-L-leucine (13.4 mg, 0.08 mmol) in anhyd
THF (2 mL) cooled at 0 °C was added DIAD (17.1 mg, 0.08 mmol)
via a syringe. The mixture was then stirred at r.t. overnight. Remov-
al of solvent under reduced pressure followed by flash chromatog-
raphy afforded 1 as white crystals; yield: 31.5 mg (90%); mp 39–41
°C.
[a]D20 –33.2 (c 0.85, CHCl3).
Rf = 0.2 (silica gel, 20% EtOAc–hexane).
1H NMR (200 MHz, CDCl3): d = 8.23 (s, 1 H), 6.05 (d, J = 8.5 Hz,
1 H, NH), 5.02 (m, 1 H), 4.68 (m, 1 H), 4.28 (m, 1 H), 3.22 (dt,
J = 7.6, 3.9 Hz, 1 H), 2.25–2.11 (m, 1 H), 2.02 (m, 1 H), 1.80–1.15
(m, 33 H), 0.95 (d, J = 5.2 Hz, 6 H), 0.87 (distorted t, 6 H).
13C NMR (75 MHz, CDCl3): d = 171.9, 170.8, 160.7, 74.8, 72.6,
56.9, 49.7, 41.4, 38.7, 34.0, 31.9, 31.2, 29.6, 29.5, 29.4, 29.3, 29.2,
28.8, 27.7, 26.8, 25.2, 24.9, 22.8, 22.7, 22.5, 21.7, 14.1, 14.0.
(3S,4S)-3-Hexyl-4-[(2R)-2-(methoxymethoxy)tridecyl]oxetan-2-
one (18)
To a soln of 16 (360 mg, 0.83 mmol) in THF–MeOH–H2O (3:1:1,
5 mL) at 0 °C was added LiOH·H2O (350 mg, 8.3 mmol) in one por-
tion and the mixture stirred for 1 h and the temperature allowed to
rise from 0 °C to r.t.. It was then acidified with 1 M HCl at 0 °C to
pH 2 and diluted with EtOAc (10 mL) and washed with brine (5
mL), dried (Na2SO4), and concentrated in vacuo. The crude acid 17
was used directly in the next reaction.
MS (ESI): m/z = 496 (M + H).
HRMS (ESI): m/z [M+ + H] calcd for C29H54NO5: 496.4001; found:
To a stirred soln of acid 17 in anhyd pyridine (10 mL) cooled at 0 °C
was added, dropwise via a syringe, PhSO2Cl (0.18 mL, 1.43 mmol).
The light yellow soln was stirred at 0 °C overnight and then diluted
with Et2O (30 mL). H2O (20 mL) was added, and the aqueous layer
was extracted with Et2O (3 × 25 mL). The combined organic layers
were washed once with H2O (15 mL) and dried (anhyd Na2SO4).
The residue was subjected to column chromatography to afford 18;
yield: 210 mg (66% over two steps).
496.3994.
Acknowledgement
K.V.R. thanks CSIR, New Delhi for the award of a fellowship.
References
[a]D25 –9.34 (c 0.45, CHCl3).
(1) (a) Weibel, E. K.; Hadvary, P.; Hochuli, E.; Kupfer, E.;
Lengsfeld, H. J. Antibiot. 1987, 40, 1081. (b) Hochuli, E.;
Kupfer, E.; Maurer, R.; Meister, W.; Mercadal, Y.; Schmidt,
K. J. Antibiot. 1987, 40, 1086.
(2) (a) Barbier, P.; Schneider, F.; Widmer, U. Helv. Chim. Acta
1987, 70, 1412. (b) Barbier, P.; Schneider, F.; Widmer, U.
Helv. Chim. Acta 1987, 70, 196. (c) Barbier, P.; Schneider,
F. J. Org. Chem. 1988, 53, 1218. (d) Dirat, O.; Kouklovsky,
C.; Langlois, Y. Org. Lett. 1999, 1, 753. (e) Ghosh, A. K.;
Liu, C. Chem. Commun. 1999, 1743. (f) Paterson, I.;
Doughty, V. A. Tetrahedron Lett. 1999, 40, 393.
Rf = 0.4 (silica gel, 10% EtOAc–hexane).
IR (neat): 2926, 1824 (C=O lactone), 1730, 1271, 1038 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.62 (q, J = 14.9, 8.31 Hz, 2 H),
4.38 (m, 1 H), 3.67 (m, 1 H), 3.35 (s, 3 H), 3.15 (m, 1 H), 1.80–1.67
(m, 2 H), 1.61–1.46 (m, 2 H), 1.26 (m, 28 H), 0.88 (m, 6 H).
13C NMR (75 MHz, CDCl3): d = 171.3, 95.9, 75.1, 74.5, 56.5, 55.6,
39.9, 34.7, 31.8, 29.6, 29.5, 29.2, 28.9, 27.6, 26.7, 24.8, 22.6, 22.4,
14.0.
MS (ESI): m/z = 399 (M+ + H).
(g) Wedler, C.; Costisella, B.; Schick, H. J. Org. Chem.
1999, 64, 5301. (h) Parsons, P. J.; Cowell, J. K. Synlett
2000, 107. (i) Ghosh, A. K.; Fidanze, S. Org. Lett. 2000, 2,
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Aust. J. Chem. 2003, 56, 795. (k) Bodkin, J. A.; Humphries,
E. J.; McLeod, M. D. Tetrahedron Lett. 2003, 44, 2869.
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Jurczak, J. Tetrahedron Lett. 2004, 45, 3873. (n) Yadav, J.
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(3S,4S)-3-Hexyl-4-[(2R)-2-hydroxytridecyl]oxetan-2-one (19)
A stirred soln of compound 18 (130 mg, 0.320 mmol) in CH2Cl2 (4
mL) was cooled to 0 °C and treated with BF3·OEt2 (28.5 mg, 0.20
mmol) and ethane-1,2-dithiol (75.7 mg, 0.8 mmol). The resulting
mixture was stirred at 0 °C for 1 h and then quenched with aq
NaHCO3 soln (2 mL), and the aqueous layer was extracted with
Et2O (2 × 5 mL). The combined organic extracts were washed with
brine (3 mL), dried (Na2SO4), and concentrated in vacuo. Column
chromatography (silica gel) of the crude product afforded 19 as a
white solid; yield: 101.7 mg (88%); mp 61–62 °C.
(3) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. B.; Satyanarayana,
M. Tetrahedron Lett. 2002, 43, 7009.
(4) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin
Trans. 1 1975, 1574.
[a]D25 –41.3 (c 0.9, CHCl3).
Rf = 0.6 (silica gel, 20% EtOAc–hexane).
IR (KBr): 2924, 2854, 1730, 1461, 1273, 1078, 967 cm–1.
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PAPER
(5) Kotsuki, H.; Kadota, I.; Ochi, M. J. Org. Chem. 1990, 55,
(8) (a) Frater, G. Helv. Chim. Acta 1979, 62, 2825. (b) Frater,
G.; Muller, U.; Gunther, W. Tetrahedron 1984, 40, 1269.
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S. J. Org. Chem. 1995, 60, 4419. (b) Fuji, K.; Kawabata, T.;
Fujita, E. Chem. Pharm. Bull. 1980, 28, 3662.
4417.
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(7) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(10) Mitsunobu, O. Synthesis 1981, 1.
Synthesis 2006, No. 22, 3888–3894 © Thieme Stuttgart · New York